Refining Treatments for Macular Disease

Bevacizumab vs Intravitreal Dexmethasone for DME

A slow release steroid injected every 16 weeks into the eyes of people with diabetic macular edema (DME) achieved similar rates of improvement in visual acuity as eyes treated with four-weekly injections of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab, according to 12-month results from a randomised controlled trial. This was the first time that a direct comparison has been drawn between a slow-release steroid formulation made specifically for ophthalmic use with an anti-VEGF treatment for DME.

DME is the most common cause of visual loss in people with diabetic retinopathy and affects approximately 6.8 per cent of people with diabetes.

The Bevordex Study, led by Professor Mark Gillies, enrolled 88 eyes of 61 patients from New South Wales, Victoria and Western Australia with centre involving DME. Forty-two eyes were randomised to receive bevacizumab (1.25 mg) every four weeks and 46 eyes randomised to receive a dexamethasone implant (0.7 mg) every 16 weeks, both pro re nata. Some patients, with two eyes treated, received treatment with both agents.

triamcinolone acetonide may be beneficial for treatment of retinal diseases such as Macular Telangiectasis type 2; age related macular degeneration and diabetic retinopathy

Dexamethasone is a sustained release steroid delivered by intravitreal injection to treat posterior segment disease. According to the study, published in Ophthalmology, the implant “consists of micronized dexamethasone in a biodegradable copolymer of polyactic-co-glycolic acid”. The implant is said to release slowly over six months although it was noted in the published report that its clinical efficacy was limited to four months in most eyes.

Figure 1. This graph shows the mean improvement in visual acuity between bevacizumab and dexamethasone (DEX) implant treated eyes. There was no statistically significant difference in the mean improvement in visual acuity between the two treatments at 12 months.

Positive Results

Researchers measured the percentage of eyes in which best-corrected visual acuity (BCVA) improved by 10 or more letters at the 48-week visit, or the 50-week visit for patients who received further treatment at 48 weeks to ensure an adequate level of the drug in the patient’s eye. Additionally they measured the two groups for any change in mean BCVA relative to the baseline level (taken at the time of the first injection) as well as mean central macular thickness (CMT), mean change in CMT and the number of injections administered throughout the treatment period.

The Impact of Vision Impairment questionnaire, which measures a patient’s perceived vision-related restriction on their level of activity and quality of life, was used to gather further data.

Ninety-two percent of the enrolled patients (81 eyes of 56 patients) completed the 12-month trial and data collected showed no significant difference in mean primary outcome BCVA scores between the two groups at 48 and 50 weeks. Seventeen of the 42 eyes (40 per cent) treated with bevacizumab and 19 of the 46 eyes (41 per cent) treated with a dexamethasone implant had a gain of 10 letters or more. Of the 42 eyes treated with bevacizumab, 13 (31 per cent) gained 15 letters or more compared with 10 (22 per cent) of the eyes treated with a dexamethasone implant. The mean improvement of BCVA for eyes treated with bevacizumab was 8.9 letters (95 per cent confidence level, 6.27 – 11.6) and 5.6 letters for eyes treated with a dexamethasone implant (95 per cent confidence level, 0.90 – 10.3).

Measurement of the change in CMT was significantly different for the two treatment groups, with a mean change in CMT of –122um for the bevacizumab group and –187um for the dexamethasone implant group. The CMT in eyes that received a dexamethasone implant clearly peaked at the four and eight month visits, which according to the study, indicated the time at which the therapeutic effect wore off in most eyes.

The number of treatments received by the two groups was significantly different with eyes treated with bevacizumab having a mean of 8.6 and eyes treated with a dexamethasone implant receiving a mean of 2.7 injections within the 12-month trial period.

Eighty-four per cent of patients completed a patient outcomes questionnaire, and reported a significant improvement in quality of life and level of activity. Twenty-five responses were collected from patients who received both treatments with eight (33 per cent) indicating they preferred the bevacizumab treatment and 11 (46 per cent) indicating they preferred the dexamethasone implant. Five (21 per cent) had no preference.

Adverse Events

Forty six per cent of eyes that received a dexamethasone implant and 19 per cent of eyes treated with bevacizumab experienced an intraocular pressure (IOP) elevation of at least 5 mmHg from baseline during the first year of the study. Twelve eyes (all treated with a dexamethasone implant) demonstrated an IOP of more than 25 mmHg at least once during follow-up visits. Eleven per cent of dexamethasone implant treated eyes lost some vision, primarily due to cataract. Progression of cataract by two grades occurred in 14.5 per cent of eyes and cataract extraction was performed on three dexamethasone implant treated eyes and one bevacizumab treated eyes. The study authors notes that “it is well–established that steroid-related cataract generally occurs in the second-year after commencing intravitreal steroid therapy so this rate is likely to increase in the second year of the trial”.

Figure 2: Curve showing the mean visual acuity over 24 month of treatment for the 1,198 eyes treated under the Treat & Extend regimen.

The researchers said the fact that the dexamethasone implant required fewer injections and fewer visits to the ophthalmologist must be weighed up against the “substantially greater cost” of this drug as well as “the clinical consequences of cataract and its removal, which is more likely in eyes receiving steroids than in those receiving VEGF inhibitors”.

The authors noted that the small size of the study and relatively short trial period were limiting factors to this study, which would continue into a second year.

Comment

This study has gained international prominence, having been invited to the Late Breaking session of the American Academy’s ‘Retina Day’ because it is the first direct comparison of two of the most commonly used agents available to treat DME. Avastin is available practically everywhere, whereas the dexamethasone implant has or is being registered in most countries for DME. Steroid-related adverse events, especially intraocular pressure rise, were relatively common. Consistent with other studies of VEGF inhibitors for DME, the bevacizumab-treated eyes had a low risk of loss of vision, whereas this did occur in a significant number of steroid-treated eyes, mostly due to cataract which is treatable. Ultimately the study provides support for considering the dexamethasone implant in pseudophakic eyes.

Reference

Mark C. Gillies, MBBS, PhD, Lyndell L. Lim, MBBS, Anna Campain, PhD, Godfrey J. Quin, MBChB, PhD, Wedad Salem, MB BS, MPH, Ji Li, MB BS, Stephanie Goodwin, BAppSc (Orthoptics) (Hons), Christine Aroney, MBBS, Ian L. McAllister, MBBS, Samantha Fraser-Bell, MBBS, PhD. A Randomized Clinical Trial of Intravitreal Bevacizumab versus Intravitreal Dexamethasone for Diabetic Macular Edema. Ophthalmology Volume 121, Number 12, December 2014.

Treat and Extend VEGF Therapy Studied

A Treat and Extend (T&E) approach to treating previously untreated eyes that have neovascular age-related macular degeneration (nAMD) can produce results that are as good as other approaches – while decreasing the burden of treatments and clinic visits. This is according to a study completed by Australian and New Zealand ophthalmologists in their community retinal practices and published in Ophthalmology.

Professor Mark Gillies from Save Sight Institute led the research, which analysed data extracted from the Fight Retinal Blindness observational registry on 1,198 treatment naïve eyes of 1,011 patients treated between January 2007 and December 2012 with a 24-month follow up.

Treat and Extend is a treatment approach that aims to decrease the number of both clinic visits and injection treatments by managing treatment based on assessed disease activity. This approach initially continues treatment irrespective of choroidal neovascular lesion (CNV) activity. Intervals between treatments
are gradually increased once CNV has been stabilised with the aim being to
keep the lesion inactive with the fewest possible treatments.

This approach differs markedly from a fixed monthly treatment schedule and pro re nata (PRN) in which monthly monitoring is required but treatment therapy is withheld unless there are
signs of activity of the CNV.

Anti-Vegf Options

In the current study, the choice of anti-vegf for treatment was made by the ophthalmologist although because ranibizumab has been funded in Australia since 2006 and aflibercept only since December 2012, ranibizumab was the predominant drug used.

Forty-nine per cent of eyes received monotherapy with ranibizumab; 2 per cent received bevacizumab monotherapy and no eyes received aflibercept monotherapy. Forty-nine per cent of eyes received a combination of two or more agents: of these injections, 9.2 per cent were bevacizumab, 7.9 per cent were aflibercept and 82.9 per cent were ranibizumab.

Treatment Frequency

Seventy-two per cent of eyes were treated at four weekly intervals for the first three months until signs of CNV activity had resolved. The treatment interval was then extended by one to two weeks as long as vision acuity (VA) remained stable (within five letters of best VA achieved) and Optical Coherence Tomography showed no signs of CNV activity. Treatment intervals were shortened if any sign of CNV occurred.

From four to six months, 59 per cent of eyes had extended to between five and eight weekly injections. From six months, around one third of eyes (21–29 per cent) were treated nine to 15 weekly. A small proportion of eyes (up to 5 per cent) were treated with an interval of 16 or more weeks.

Eyes were treated at nearly 80 per cent of visits at which lesions were graded as inactive. The researchers identified a peak mean gain of visual acuity of +6.4 letters after initiating treatment, which gradually subsided to a gain of +5.1 letters at 24 months. They noted that the proportion of eyes with visual acuity of 20/40 or better increased from 27 per cent at baseline to 45 per cent after two years of treatment. Two-year mean visual acuity gains improve over time from 2007 to 2012, coinciding with an overall upward trend in the mean total number of injections per year over two years. There was a mean of 7.5 injections per eye in the first year and 5.5 in the second while the mean number of visits was only slightly higher at 7.9 in the first year and 6.7 in the second.

Vision Outcomes

The report stated: “the mean initial VA of the 1,198 eyes that completed the 24-month follow-up (56.5 letters) was significantly better than that of the eyes with less than 24 months follow-up (48.4 [20/120+3]; t-test P<0.001). Likewise, the proportion of eyes with an initial VA of 70 letters (20/40) or better was greater for eyes with more than 24 months follow-up (27 per cent) than for eyes lost to follow-up (17 per cent; P<0.001). Patients with less than 24 months follow-up were a little older at initial visit (80.8 vs 79.4 years; P=0.01). There was no difference between the lesion types for eyes with 24 months follow up and those with shorter follow-up (P=0.84)”.

They concluded that despite the patient group being unselected and subject to treatment constrains from patient co-morbidities, “despite the vagaries of routine clinical practice… we have been able to demonstrate here that a T&E regimen can produce good results with fewer visits than other approaches”.

Comment

Whilst some people have claimed to ‘invent’ the T&E regimen for intravitreal injection, really it is just common sense to control a pathological process with a more intense ‘induction’ phase then control it with a less intense ‘maintenance phase’, as we do, for example, for uveitis. Many Australian ophthalmologists recognised this and used a T&E regimen from when they first started in 2006 to treat neovascular AMD. Most Americans and Europeans started with a PRN regimen in which they only treated if there was macular oedema or other signs of activity of the invading neovascular membrane. More recently, T&E has become more common internationally but with very little scientific evidence. This study is the largest series with two-years follow up yet reported. The T&E nature of treatment was verified by the finding that 80 per cent of eyes received an injection of drug when they were graded as inactive, whereas for PRN treatment this would be 0 per cent. A significant gain of one line of vision was found after two years of treatment with a mean of 13 injections. This is a very good outcome, particularly compared with similar reports from the United Kingdom and the United States where fewer injections tend to be given and initial gains in mean visual acuity are usually lost by two years. Interestingly, we found that vision gains improved over time since 2006 in association with an increased number of injections.

Reference

Jennifer J Arnold MB BS (Hons), Anna Campain PhD, Daniel Barthelmes MD PhD, Judy M Simpson, PhD, CStat, Robyn H Guymer MB BS, PhD5, Alex P Hunyor MB BS, Ian L McAllister MB BS, Rohan W Essex MB BS, Nigel Morlet MB BS, Mark C Gillies MB BS, PhD, and the Fight Retinal Blindness Study Group.

Two Year Outcomes of ‘Treat And Extend’ Intravitreal Therapy for Neovascular Age-Related Macular Degeneration

Effect of Triamcinolone Acetonide on Retinal Disease

Researchers have found that triamcinolone acetonide (TA) may be beneficial for treatment of retinal diseases such as Macular Telangiectasis type 2 (MacTel); age related macular degeneration (AMD) and diabetic retinopathy (DR).

The findings were published in a research article entitled Effect of Glucocorticoids on Neuronal and Vascular Pathology in a Transgenic Model of Selective Müller Cell Ablation, in Wiley Periodicals (2014).¹

In this study designed by Weiyong Shen from Save Sight Institute, researchers injected TA in a transgenic model four days before commencing Müller cell ablation to examine the effects and underlying mechanisms of glucocorticoid treatment on photoreceptor degeneration and retinal vascular pathology.

The transgenic model had previously been developed to study the effect of selective ablation of Müller cells. In this earlier study, reported in The Journal of Neuroscience, researchers reported that cell ablation “led to photoreceptor apoptosis, vascular telangiectasis, blood–retinal barrier breakdown and, later, intraretinal neovascularization”.² They found that “these changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors.”

Figure 3. Intravitreal triamcinolone acetonide (TA) protects photoreceptors and inhibits retinal vascular leak after Muller cell ablation. (A, D): Eyes injected with TA had many more photoreceptors (red) and less infiltration of microglia (green) than controls injected with balanced salt (BSS). Fluorescein angiography was performed before (B, E) and after treatment with TA or BSS (C, F). Arrows in (B, C and E) point to vascular leak arising after Müller cell ablation. Note complete suppression of vascular leak after TA treatment in (F).

Despite their different etiologies, researchers understand that vision loss in MacTel, AMD and DR is ultimately associated with damage to the photoreceptor caused by the breakdown of the blood-retinal barrier (BRB) and neovascularisation. There is currently no way to treat or prevent this degeneration.

In an effort to better understand the effect of TA on these retinal diseases, the researchers examined: changes in photoreceptors, microglia and Müller cells, retinal vasculature, differential expression of p75 neurotrophin receptor (p75NTR), tumor necrosis factor-a (TNFα), the precursor and mature forms of neurotrophin 3 (pro-NT3 and mature NT3) and activation of the p53 and p38 stress-activated protein kinase (p38/SAPK) signaling pathways.¹

As a result of their study, the researchers reported that “TA prevented photoreceptor degeneration and inhibited activation of microglial and Müller cells. TA attenuated Müller cell loss and inhibited overexpression of p75NTR, TNFα, pro-NT, and the activation of p53 and p38/SAPK signaling pathways. TA not only prevented the development of retinal vascular lesions but also inhibited fluorescein leakage from established vascular lesions. TA inhibited overexpression of VEGF in transgenic mice but without affecting its basal level expression in the normal retina.”¹

The authors proposed that further pre-clinical testing was justified, having found that “treatment with the glucocorticoid, TA, can prevent photoreceptor degeneration and the development of retinal vasculopathy in a novel transgenic model”.¹

Comment

We have been interested in the role that Muller cells might play in retinal disease since we found that they were missing from the central macula of an eye with Idiopathic Macular Telangiectasia type 2 (MacTel). The involvement of Muller cells in the pathogenesis of other retinal diseases, such as diabetic retinopathy, has long been suspected but is still poorly understood because the cells are difficult to study. We developed a transgenic mouse in which the Muller cells of adult mice could be inducibly knocked out. This resulted in retinal vascular disease (leak, neovascularisation) and photoreceptor degeneration, the latter process being the final common pathway to blindness in most retinal diseases. While the steroid abrogated retinal vascular leak, which was expected because it is used clinically for macular oedema, it also inhibited photoreceptor degeneration. This result is clinically significant because we already know that neuronal degeneration is a prominent aspect of diabetic macular oedema. If these eyes receive intravitreal therapy it will often be long-term and either with a VEGF inhibitor or a steroid. Whether either class of drug can prevent photoreceptor degeneration might be a point of difference between the two. Our studies in this model suggest that VEGF inhibitors are not neuroprotective, but we can only develop hypotheses from animal studies, the potential neuroprotective effects of steroids is something that warrants further study in clinical trials.

References:

1. Weiyong Shen, So-Ra Lee, Joana Araujo, Sook H. Chung, Ling Zhu, and Mark C. Gillies. Effect of Glucocorticoids on Neuronal and Vascular Pathology in a Transgenic Model of Selective Müller Cell Ablation. 2014 Wiley Periodicals, Inc. wileyonlinelibrary.com. DOI: 10.1002/glia.22666


2. Weiyong Shen, Marcus Fruttiger, Ling Zhu, Sook H. Chung, Nigel L. Barnett, Joshua K. Kirk, SoRa Lee,
Nathan J. Coorey, Murray Killingsworth, Larry S. Sherman, and Mark C. Gillies. Conditional Müller Cell Ablation Causes Independent Neuronal and Vascular Pathologies in a Novel Transgenic Model. The Journal of Neuroscience, November 7,